title: Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy.
abstract: For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Lhériteau
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Lolita
authors.initials: L
authors.lastname: Petit
authors.affiliation: CHU-Hôtel Dieu, Service d'Ophtalmologie, Nantes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Weber
authors.affiliation: CHU-Hôtel Dieu, Service d'Ophtalmologie, Nantes, France.
authors.forename: Guylène
authors.initials: G
authors.lastname: Le Meur
authors.affiliation: ONIRIS, Nantes-Atlantic College of Veterinary Medicine Food Science and Engineering, Emergency and Critical Care Unit, Nantes, France.
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Lyse
authors.initials: L
authors.lastname: Libeau
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mendes-Madeira
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Guihal
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Achille
authors.initials: A
authors.lastname: François
authors.affiliation: CNRS UMR 6061, Université de Rennes 1, Rennes, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Guyon
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Provost
authors.affiliation: Clinique Vétérinaire Atlantia, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lemoine
authors.affiliation: Institut Pasteur, INSERM UMRS 1120, Paris, France.
authors.forename: Samantha
authors.initials: S
authors.lastname: Papal
authors.affiliation: Institut Pasteur, INSERM UMRS 1120, Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: El-Amraoui
authors.affiliation: INRA/ONIRIS, Nantes-Atlantic College of Veterinary Medicine Food Science and Engineering, Nantes, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France; Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.affiliation: INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France. Electronic address: fabienne.rolling@inserm.fr.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rolling
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D005136:Eye Proteins / Q000235:genetics*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D023061:Gene Order; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D005136:Eye Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins